Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upregulation of calpain, a Ca(2+)-activated cysteine protease, has been implicated in apoptosis and tissue degeneration in spinal cord injury (SCI) that over time spreads from the site of injury to the surrounding regions. We examined calpain content and activity, regulation of immediate early genes (IEGs) such as c-jun and c-fos, reactive astrogliosis as the expression of glial fibrillary acidic protein (GFAP), and apoptosis-related features such as caspase-3 mRNA expression and internucleosomal DNA fragmentation in 1-cm long spinal cord segments (S1, distant rostral; S2, adjacent rostral; S3, lesion or injury; S4, adjacent caudal; and S5, distant caudal) following SCI in rats. Calpain content and production of 150 kD calpain-cleaved alpha-fodrin fragment, expression of IEGs, reactive astrogliosis, and apoptotic features were highly increased in the lesion (S3), moderately in adjacent areas (S2 and S4), and slightly in distant areas (S1 and S5) in SCI rats when compared to sham animals. Administration of the calpain-specific inhibitor E-64-d (1 mg/kg) to SCI rats continuously for 24 h inhibited calpain activity and other factors contributing to apoptosis in the lesion and surrounding areas, indicating that calpain played a key role in the pathophysiology of SCI. The results obtained from this animal model of SCI suggest that calpain inhibitor can provide neuroprotection in patients with SCI.
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PMID:Inhibition of calpain-mediated apoptosis by E-64 d-reduced immediate early gene (IEG) expression and reactive astrogliosis in the lesion and penumbra following spinal cord injury in rats. 1159 98

Excitotoxic glutamate CNS stimulation can result in neuronal cell death. Contributing mechanisms and markers of cell death are the activation of caspase-3 and DNA fragmentation. It remains to be resolved to which extent both cellular reactions overlap and/or indicate different processes of neurodegeneration. In this study, mixed neuronal cultures from newborn mice pubs (0-24 h) were stimulated with glutamate, and the co-localization of active caspase-3 and DNA fragmentation was investigated by immunocytochemistry and the TUNEL nick-end labelling. In untreated cultures, 8% scattered neurons (marked by MAP-2) displayed activated caspase-3 at different morphological stages of degeneration. TUNEL staining was detected in 5% of cell nuclei including GFAP-positive astrocytes. However, co-localization of active caspase-3 with TUNEL was less than 2%. After glutamate stimulation (125 microM), the majority of neurons was dying between 12 and 24 h. The absolute number of active caspase-3 neurons increased only moderately but in relation of surviving neurons after 24 h from 8 to 36% (125 microM), to 53% (250 microM) or to 32% (500 microM). TUNEL staining also increased after 24 h following glutamate treatment to 37% but the co-localization with active caspase-3 remained at the basal low level of 2%. In our system, glutamate-mediated excitotoxicity effects the DNA fragmentation and caspase-3 activation. Co-localization of both parameters, however, is very poor. Active caspase-3 in the absence of TUNEL indicates a dynamic degenerative process, whereas TUNEL marks the end stage of severe irreversible cell damage regardless to the origin of the cell.
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PMID:Caspase-3 activation and DNA fragmentation in primary hippocampal neurons following glutamate excitotoxicity. 1159 62

Oxidative stress mediated by nitric oxide (NO) and its toxic metabolite peroxynitrite has previously been associated with motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Degenerating spinal motor neurons in familial and sporadic ALS are typically surrounded by reactive astrocytes expressing the inducible form of NO synthase (iNOS), suggesting that astroglia may have a pathogenic role in ALS. We report here that a brief exposure of spinal cord astrocyte monolayers to peroxynitrite (0.25-1 mM) provoked long-lasting reactive morphological changes characterized by process-bearing cells displaying intense glial fibrillary acidic protein and iNOS immunoreactivity. Furthermore, peroxynitrite caused astrocytes to promote apoptosis of embryonic motor neurons subsequently plated on the monolayers. Neuronal death occurred within 24 hr after plating, as evidenced by the presence of degenerating motor neurons positively stained for activated caspase-3 and nitrotyrosine. Motor neuron death was largely prevented by NOS inhibitors and peroxynitrite scavengers but not by trophic factors that otherwise will support motor neuron survival in the absence of astrocytes. The bacterial lipopolysaccharide, a well-known inflammatory stimulus that induces iNOS expression in astrocytes, provoked the same effects on astrocytes as peroxynitrite. Thus, spinal cord astrocytes respond to extracellular peroxynitrite by adopting a phenotype that is cytotoxic to motor neurons through peroxynitrite-dependent mechanisms.
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PMID:Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis. 1175 77

Neural precursor cells (NPCs) populate the embryonic ventricular zone and persist in the subependymal zone of the adult brain. We hypothesized that hereditary and/or acquired mutations in apoptosis-associated genes, such as p53 and caspases, may protect NPCs from DNA damage-induced death and predispose them to subsequent neoplastic transformation. To test this hypothesis, we exposed NPCs from wild-type and targeted gene-disrupted mouse embryos (p53, caspase-9, caspase-3, and bax mutants) to ethyl-nitrosourea (ENU), a known DNA mutagen and neural carcinogen, and measured NPC viability. We found that ENU produced caspase-3 activation and apoptotic NPC death 6-24 h after administration both in vivo and in vitro. This effect was critically dependent on p53 and caspase-9 expression. The long-term effect of intrauterine ENU exposure was examined in control and p53-deficient mice. High grade glial tumors were found in 60% of p53(-/-) young adult mice exposed to ENU on gestational day 12.5 but not in p53(+/-) or p53(+/+) littermates or in untreated p53-deficient mice. All the tumors were located supratentorially and possessed strong immunoreactivity for glial fibrillary acidic protein and the anti-apoptotic molecule Bcl-X(L). These results suggest that intrauterine exposure of NPCs to certain DNA damaging agents may synergistically interact with specific genetic abnormalities (e.g. p53 deficiency) to produce glial neoplasms in the adult brain.
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PMID:Neural precursor cell apoptosis and glial tumorigenesis following transplacental ethyl-nitrosourea exposure. 1178 43

The subventricular zone of the adult mammalian brain harbors the neural stem cell population with potential neural regeneration and repair capacity. We describe a nonviral technique to preferentially transfect in vivo the adult neural stem cell population and its immediate progeny based on intraventricular injection of PEI/DNA complexes. The transfected population was identified by cellular and ultra-structural evidence showing their proliferating status and expression of the specific markers GFAP and nestin. Stable activation of the lacZ reporter by cre-recombinase transfection in R26R mice demonstrated survival and migration of stem cell derivatives three months after injection. Apoptosis is thought to be the most common fate of the stem cell progeny. Overexpression of Bcl-X(L) increased number and survival time of transduced progenitors and decreased the frequency of cells immunopositive for activated Caspase-3. This method thus provides selective targeting of the stem cell population and should allow an in-depth understanding of their biology.
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PMID:Preferential transfection of adult mouse neural stem cells and their immediate progeny in vivo with polyethylenimine. 1186 Feb 70

The pathogenesis of six pigeon-origin isolates of Newcastle disease virus (NDV) was investigated in chickens. Four isolates were previously defined as the variant pigeon paramyxovirus 1 (PPMV-1), and two isolates were classified as avian paramyxovirus 1 (APMV-1). Birds inoculated with PPMV-1 isolates were euthanatized, and tissue samples were collected at 2, 5, and 10 days postinoculation (DPI). Birds inoculated with APMV-1 isolates died or were euthanatized, and tissue samples were collected at 2, 4, and 5 DPI. Tissues were examined by histopathology, immunohistochemistry (IHC) for the presence of NDV nucleoprotein, and in situ hybridization (ISH) for the presence of viral mRNA for the matrix gene. Spleen sections were stained by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and by IHC using an anti-active caspase-3 antibody (IHC-Casp) to detect apoptotic cells. Brain sections of PPMV-1-infected birds were examined by IHC to detect T and B lymphocytes and glial fibrillary acidic protein (GFAP). Histologically, birds inoculated with PPMV-1 isolates had marked lesions in the heart and brain. Presence of viral nucleoprotein and viral mRNA in the affected tissues was confirmed by IHC and ISH, respectively. Numerous reactive astrocytes were observed in brain sections stained for GFAP Among all the isolates, the IHC-Casp demonstrated that apoptosis was very prominent in the ellipsoid-associated cells of the spleen at 2 DPI. Results of the TUNEL assay indicated that apoptotic cells were prominent at 5 DPI and were more randomly distributed. The clinical signs and gross and histopathologic changes observed in the APMV-1-infected birds were characteristic of an extensive infection with highly virulent NDV evident by IHC.
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PMID:Pathogenesis of six pigeon-origin isolates of Newcastle disease virus for domestic chickens. 1201 99

Cerebral white matter lesions in Alzheimer's disease (AD) consist of subcortical degeneration and ischaemic-hypoxic changes. Glial changes are intimately associated with the white matter lesions, and regressive changes in astrocytes and loss of oligodendroglial cells have been reported. We quantitatively compared glial changes including apoptosis and enhanced lysosomal activity in the frontal and temporal white matter by using terminal dUTP nick end labelling (TUNEL) and immunohistochemistry for glial markers, lysosomes and apoptosis-regulating proteins in non-familial AD brains. The degree of myelin pallor and axonal loss varied considerably in both the frontal and temporal white matter but fibrillary gliosis in demyelinated lesions tended to be less prominent in the temporal white matter in AD cases. A morphometric study with planimetric methods for cross-sectional areas of frontal and temporal white matter revealed that the white matter of AD cases manifested atrophy with significant reduction in frontal (11.9%) and temporal (29.4%) white matter compared to normal controls. Double immunolabelling for glial fibrillary acidic protein (GFAP) and KP1 (CD68) revealed KP1-positive fragmented structures within the weakly GFAP-labelled astrocytes. These KP1-positive structures correspond to process fragmentation and cytoplasmic vacuoles, which in turn indicate enhanced lysosomal activity during regressive changes in astrocytes. The KP1-modified astrocytes were not found in Pick's disease and corticobasal degeneration. The density of apoptotic glial cells, largely oligodendroglial, was significantly higher in the temporal than in the frontal white matter, and most GFAP-positive astrocytes with regressive changes were apoptotic. GFAP-positive astrocyte density was statistically the same in the frontal and temporal white matter, but the density of KP1-modified astrocytes was higher in the temporal than in the frontal white matter. The rate of white matter shrinkage was significantly correlated with the density of apoptotic glial cells and the density of KP1-modified astrocytes in the temporal lobe in AD cases. An increase in apoptotic glial cell density was found to contribute to GFAP-positive astrocytes with regressive changes in temporal white matter, while apoptosis of vascular smooth muscle cells did not show topographical accentuation. Astrocytes labelled with beta amyloid protein were not apoptotic, and the density of apoptotic cells labelled with CD95 and caspase-3 was too low in both types of white matter to be statistically evaluated. Our results imply that regressive changes in astrocytes and glial apoptosis are, to some extent, associated with white matter lesions, particularly of the temporal lobe in AD brains. The presence of apoptotic astrocytes with evidence of regressive change could therefore be a histological hallmark for white matter degeneration in AD.
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PMID:Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer's disease. 1206 Mar 48

We have previously demonstrated that estradiol reduces cell death in cortical explant cultures following injury induced by metabolic inhibition in a receptor-dependent fashion. In this study, we examined whether cell death involves apoptosis and assessed the potential mediators of estradiol's actions. Cortical explant cultures were generated from postnatal day 3 rat pups. On day 7 in vitro, explants were injured by exposure to 1 mM 2-DG/2 mM KCN for 2 h to model the metabolic inhibition observed during ischemia. Explants were fixed in 4% paraformaldehyde at 2, 6, 10 and 24 h following the injury period and 18-microm thick sections were cut on a cryostat and stained with cresyl violet to assess cell death. The same sections were also labeled by TUNEL to determine whether cell death occurred by apoptosis. Other sections were used for immunohistochemistry to determine whether cells that stained positive for activated caspase 3 were also immunopositive for NeuN, a neuronal marker, or GFAP, an astrocyte marker. Protein was extracted for Western blot analysis from a separate set of explants collected at 0, 0.5, 1, 2 and 4 h following the conclusion of the injury. Estradiol treatment significantly reduced the number of cells undergoing apoptotic cell death as indicated by nuclear condensation visualized by cresyl violet staining (P<0.05). TUNEL staining revealed that the majority of pyknotic and fragmented nuclei were also TUNEL positive. Furthermore, caspase 3 activation appeared to be restricted to neurons. To examine a possible mechanism by which estradiol prevents apoptosis, we examined the level of activation of Akt kinase, which mediates antiapoptotic signals. Potential activation was measured by phosphorylation of Akt at Ser473 by Western blot analysis. In the absence of estradiol, pAkt levels were significantly increased at 2 h following the termination of injury. Explants that were pretreated with estradiol exhibited elevated levels of pAkt at 1 h following injury. Treatment with ICI 182,780 prevented the effect of estradiol. These studies suggest that estradiol prevents injury-induced apoptosis and that Akt activation may mediate these protective effects.
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PMID:Estradiol enhances Akt activation in cortical explant cultures following neuronal injury. 1219 93

Increasing data provide support for the hypothesis that inflammatory cytokines mediate inflammation-induced injury to developing white matter. In the present study, roles of tumor necrosis factor-alpha (TNFalpha) and interleukin-1 beta (IL-1beta) in mediating lipopolysaccharide (LPS)-induced brain injury were investigated by co-administration of LPS with IL-1 receptor antagonist (IL-1ra) or TNFalpha antibody in the 5-day-old rat brain. Intracerebral injection of LPS and other agents was performed in a stereotaxic apparatus at the location of 1.0 mm posterior and 1.0 mm lateral to the bregma, and 2.0 mm deep to the skull surface at the left hemisphere. Brain injury was examined in brain sections 3 and 11 days after LPS injection. LPS-induced inflammatory responses were evidenced by great increases in TNFalpha and IL-1beta concentrations in the neonatal rat brain 6 h after LPS injection. White matter rarefaction was observed in 71% (five out of seven) of the rat brains 3 days after LPS injection and bilateral ventricle dilation was found in 71% (five out of seven) of the P8 rat brains and in 100% of the P16 rat brains (four out of four). These alterations were not found in the control rat brains. No apparent histological changes in gray matter were observed in the LPS-injected rat brains. LPS injection also resulted in injuries to oligodendrocytes (OLs) and hypomyelination, as indicated by reduced immunostaining for O4 and myelin basic protein (MBP). Increased astrogliosis, as indicated by increased glial fibrillary acidic protein (GFAP) immunostaining, was also observed in the LPS-injected, but not the control rat brain. Co-administration of LPS with IL-1ra, but not with TNFalpha antibody, significantly attenuated LPS-induced white matter injury, as indicated by decreases in ventricle dilation, white matter rarefaction, GFAP positive staining and by improved O4 and MBP immunostaining. Co-administration of LPS with IL-1ra significantly reduced LPS-induced elevation of caspase-3 activity in the rat brain. While TNFalpha antibody had no effect on LPS-induced elevation of caspase-3 activity, co-administration of LPS with TNFalpha antibody partially, but significantly, decreased LPS-stimulated increase in IL-1beta in the neonatal rat brain. These data suggest that IL-1beta may play an important role in mediating LPS-induced brain injury and TNFalpha may have complicated, probably dual, effects in LPS-induced brain injury.
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PMID:Differential roles of tumor necrosis factor-alpha and interleukin-1 beta in lipopolysaccharide-induced brain injury in the neonatal rat. 1276 91

We carried out a study to determine if the high-neurovirulence GDVII strain of Theiler's murine encephalomyelitis virus (TMEV) and the demyelinating, low-neurovirulence BeAn strain induced apoptosis in murine astrocytes. Astrocytes, the major glial cell population of the central nervous system, were semipermissive for GDVII virus replication. Programmed cell death, demonstrated by apoptosis-specific caspase-3 protease activity, was maximal 8 h after GDVII infection at an m.o.i. of 1. Purified TMEV capsid proteins VP1, VP2, and VP3 did not induce apoptosis but antibodies to VP1 and VP2 inhibited it. Antibody inhibition of caspase-3 activity as well as flow cytometry experiments implicated TNF-related apoptosis-inducing ligand (TRAIL) and TNF-alpha-receptor (TNF-R) in apoptosis signaling. Conversely, TNF-alpha and the TRAIL-receptor were not upregulated. Furthermore, the number of functional TNF-alpha receptors, but not their affinity, was increased in apoptotic GDVII virus-infected astrocytes, as confirmed in binding experiments with 125I-labeled recombinant murine TNF-alpha. In vivo studies showed that most of the cells loaded with the virus when injected in the brains of SJL mice were neurons but very few showed TUNEL costaining. Conversely, many of the apoptotic cells found were also positive for GFAP staining.
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PMID:High-neurovirulence GDVII virus induces apoptosis in murine astrocytes through tumor necrosis factor (TNF)-receptor and TNF-related apoptosis-inducing ligand. 1284 25


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